Publications by authors named "Christina Reinauer"

17 Publications

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Challenges in management of transient hyperinsulinism - a retrospective analysis of 36 severely affected children.

J Pediatr Endocrinol Metab 2021 Apr 15. Epub 2021 Apr 15.

Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.

Objectives: Transient hyperinsulinism (THI) is a hypoglycemia disorder which resolves spontaneously within the first weeks or months of life. The pathomechanism of THI is not elucidated yet; however, it is known that perinatal stress predisposes for THI. We aimed to characterize the clinical phenotype and treatment of children with THI, and to identify options for improved management.

Methods: A retrospective analysis of 36 children with THI treated at the University Children's Hospital Düsseldorf between 2007 and 2019 was performed.

Results: All children had risk factors for neonatal hypoglycemia or indicators of perinatal stress. Eighty three percent were diagnosed with hypoglycemia on day of life (DOL)1. None of the six diagnosed later had routine blood glucose screening and showed significantly lower blood glucose levels at the time of first blood glucose measurement compared to the children diagnosed on DOL1. Ninety seven percent of all children received intravenous glucose, 42% received continuous glucagon and 81% were started on diazoxide. Diazoxide withdrawal and subsequent fasting tests lacked standardization and were based on clinical experience. Three patients had a subsequent episode of hypoglycemia, after fasting studies only demonstrated "clinical" remission without proving the ability to ketogenesis.

Conclusions: Any kind of perinatal stress might pose a risk to develop THI, and postnatal monitoring for hypoglycemia still needs to be improved. Diazoxide is effective in children with THI; however, further studies are needed to guide the development of criteria and procedures for the initiation and discontinuation of treatment. Furthermore, establishing consensus diagnostic criteria/definitions for THI would improve comparability between studies.
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http://dx.doi.org/10.1515/jpem-2020-0639DOI Listing
April 2021

Challenges in management of transient hyperinsulinism - a retrospective analysis of 36 severely affected children.

J Pediatr Endocrinol Metab 2021 Apr 15. Epub 2021 Apr 15.

Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.

Objectives: Transient hyperinsulinism (THI) is a hypoglycemia disorder which resolves spontaneously within the first weeks or months of life. The pathomechanism of THI is not elucidated yet; however, it is known that perinatal stress predisposes for THI. We aimed to characterize the clinical phenotype and treatment of children with THI, and to identify options for improved management.

Methods: A retrospective analysis of 36 children with THI treated at the University Children's Hospital Düsseldorf between 2007 and 2019 was performed.

Results: All children had risk factors for neonatal hypoglycemia or indicators of perinatal stress. Eighty three percent were diagnosed with hypoglycemia on day of life (DOL)1. None of the six diagnosed later had routine blood glucose screening and showed significantly lower blood glucose levels at the time of first blood glucose measurement compared to the children diagnosed on DOL1. Ninety seven percent of all children received intravenous glucose, 42% received continuous glucagon and 81% were started on diazoxide. Diazoxide withdrawal and subsequent fasting tests lacked standardization and were based on clinical experience. Three patients had a subsequent episode of hypoglycemia, after fasting studies only demonstrated "clinical" remission without proving the ability to ketogenesis.

Conclusions: Any kind of perinatal stress might pose a risk to develop THI, and postnatal monitoring for hypoglycemia still needs to be improved. Diazoxide is effective in children with THI; however, further studies are needed to guide the development of criteria and procedures for the initiation and discontinuation of treatment. Furthermore, establishing consensus diagnostic criteria/definitions for THI would improve comparability between studies.
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http://dx.doi.org/10.1515/jpem-2020-0639DOI Listing
April 2021

Worse glycemic control, higher rates of diabetic ketoacidosis, and more hospitalizations in children, adolescents, and young adults with type 1 diabetes and anxiety disorders.

Pediatr Diabetes 2021 May 2;22(3):519-528. Epub 2021 Feb 2.

Institute for Epidemiology und Medical Biometry, ZIBMT, Universität Ulm, Ulm, Germany.

The aim of the study was to explore the metabolic characteristics and outcome parameters in youth with type 1 diabetes and anxiety disorders. HbA1c levels, rates of severe hypoglycemia, diabetic ketoacidosis (DKA), and hospital admission in children, adolescents, and young adults with type 1 diabetes and an anxiety disorder from 431 diabetes-care-centers participating in the nationwide German/Austrian/Swiss/Luxembourgian diabetes survey DPV were analyzed and compared with youth without anxiety disorders. Children, adolescents, and young adults with type 1 diabetes and anxiety disorders (n = 1325) had significantly higher HbA1c (8.5% vs. 8.2%), higher rates of DKA (4.2 vs. 2.5 per 100 patient-years), and higher hospital admission rates (63.6 vs. 40.0 per 100 patient-years) than youth without anxiety disorders (all p < 0.001). Rates of severe hypoglycemia did not differ. Individuals with anxiety disorders other than needle phobia (n = 771) had higher rates of DKA compared to those without anxiety disorders (4.2 vs. 2.5 per 100 patient-years, p = 0.003) whereas the rate of DKA in individuals with needle phobia (n = 555) was not significantly different compared to those without anxiety disorders. Children, adolescents, and young adults with anxiety disorders other than needle phobia had higher hospitalization rates (73.7 vs. 51.4 per 100 patient-years) and more inpatient days (13.2 vs. 10.1 days) compared to those with needle phobia (all p < 0.001). Children, adolescents, and young adults with type 1 diabetes and anxiety disorders had worse glycemic control, higher rates of DKA, and more hospitalizations compared to those without anxiety disorders. Because of the considerable consequences, clinicians should screen for comorbid anxiety disorders in youth with type 1 diabetes.
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http://dx.doi.org/10.1111/pedi.13177DOI Listing
May 2021

Disease characteristics of MCT8 deficiency: an international, retrospective, multicentre cohort study.

Lancet Diabetes Endocrinol 2020 07;8(7):594-605

Department of Diabetes and Endocrinology, Women's and Children's Hospital, North Adelaide, SA, Australia.

Background: Disordered thyroid hormone transport, due to mutations in the SLC16A2 gene encoding monocarboxylate transporter 8 (MCT8), is characterised by intellectual and motor disability resulting from cerebral hypothyroidism and chronic peripheral thyrotoxicosis. We sought to systematically assess the phenotypic characteristics and natural history of patients with MCT8 deficiency.

Methods: We did an international, multicentre, cohort study, analysing retrospective data from Jan 1, 2003, to Dec 31, 2019, from patients with MCT8 deficiency followed up in 47 hospitals in 22 countries globally. The key inclusion criterion was genetically confirmed MCT8 deficiency. There were no exclusion criteria. Our primary objective was to analyse the overall survival of patients with MCT8 deficiency and document causes of death. We also compared survival between patients who did or did not attain full head control by age 1·5 years and between patients who were or were not underweight by age 1-3 years (defined as a bodyweight-for-age Z score <-2 SDs or <5th percentile according to WHO definition). Other objectives were to assess neurocognitive function and outcomes, and clinical parameters including anthropometric characteristics, biochemical markers, and neuroimaging findings.

Findings: Between Oct 14, 2014, and Jan 17, 2020, we enrolled 151 patients with 73 different MCT8 (SLC16A2) mutations. Median age at diagnosis was 24·0 months (IQR 12·0-60·0, range 0·0-744·0). 32 (21%) of 151 patients died; the main causes of mortality in these patients were pulmonary infection (six [19%]) and sudden death (six [19%]). Median overall survival was 35·0 years (95% CI 8·3-61·7). Individuals who did not attain head control by age 1·5 years had an increased risk of death compared with patients who did attain head control (hazard ratio [HR] 3·46, 95% CI 1·76-8·34; log-rank test p=0·0041). Patients who were underweight during age 1-3 years had an increased risk for death compared with patients who were of normal bodyweight at this age (HR 4·71, 95% CI 1·26-17·58, p=0·021). The few motor and cognitive abilities of patients did not improve with age, as evidenced by the absence of significant correlations between biological age and scores on the Gross Motor Function Measure-88 and Bayley Scales of Infant Development III. Tri-iodothyronine concentrations were above the age-specific upper limit in 96 (95%) of 101 patients and free thyroxine concentrations were below the age-specific lower limit in 94 (89%) of 106 patients. 59 (71%) of 83 patients were underweight. 25 (53%) of 47 patients had elevated systolic blood pressure above the 90th percentile, 34 (76%) of 45 patients had premature atrial contractions, and 20 (31%) of 64 had resting tachycardia. The most consistent MRI finding was a global delay in myelination, which occurred in 13 (100%) of 13 patients.

Interpretation: Our description of characteristics of MCT8 deficiency in a large patient cohort reveals poor survival with a high prevalence of treatable underlying risk factors, and provides knowledge that might inform clinical management and future evaluation of therapies.

Funding: Netherlands Organisation for Health Research and Development, and the Sherman Foundation.
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http://dx.doi.org/10.1016/S2213-8587(20)30153-4DOI Listing
July 2020

Continuous Glucose Monitoring in Adults with Type 1 Diabetes: Real-World Data from the German/Austrian Prospective Diabetes Follow-Up Registry.

Diabetes Technol Ther 2020 08 6;22(8):602-612. Epub 2020 Jul 6.

Institute of Epidemiology and Medical Biometry, ZIBMT, Ulm University, Ulm, Germany.

To analyze key indicators of metabolic control in adults with type 1 diabetes (T1D) using real-time or intermittent scanning continuous glucose monitoring (rtCGM/iscCGM) during real-life care, based on the German/Austrian/Swiss Prospective Diabetes Follow-up (DPV) registry. Cross-sectional analysis including 233 adults with T1D using CGM. We assessed CGM metrics by gender, age group (18 to <30 years vs. ≥30 years), insulin delivery method (multiple daily injections vs. continuous subcutaneous insulin infusion [CSII]) and sensor type (iscCGM vs. rtCGM), working days versus weekends, and daytime versus night-time using multivariable linear regression models (adjusted for demographic variables) or Wilcoxon signed-rank test. Overall, 79/21% of T1D patients used iscCGM/rtCGM. Those aged ≥30 years spent more time in range (TIR [70-180 mg/dL] 54% vs. 49%) and hypoglycemic range <70 mg/dL (7% vs. 5%), less time in hyperglycemic range >180 mg/dL (38% vs. 46%) and had a lower glucose variability (coefficient of variation [CV] 36% vs. 37%) compared with adults aged <30 years. We found no significant differences between genders. Multivariable regression models revealed the highest Time In Range (TIR) and lowest time with sensor glucose >250 mg/dL, CV and daytime-night-time differences in those treated with CSII and rtCGM. Glucose profiles were slightly more favorable on working days. In our real-world data, rtCGM versus iscCGM was associated with a higher percentage of TIR and improved metabolic stability. Differences in ambulatory glucose profiles on working and weekend days may indicate lifestyle habits affecting glycemic stability. Real-life CGM results should be included in benchmarking reports in addition to hemoglobin A1c (HbA1c) and history of hypoglycemia.
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http://dx.doi.org/10.1089/dia.2020.0019DOI Listing
August 2020

Course of Disordered Eating Behavior in Young People With Early-Onset Type I Diabetes: Prevalence, Symptoms, and Transition Probabilities.

J Adolesc Health 2019 11 29;65(5):681-689. Epub 2019 Aug 29.

German Diabetes Center, Institute for Biometrics and Epidemiology, Düsseldorf, Germany; German Center for Diabetes Research, München-Neuherberg, Germany.

Purpose: The aims of this study were to analyze the prevalence and course of disordered eating behavior (DEB) in adolescents with intensively treated type I diabetes, describe differences in age-specific DEB symptoms, and identify predictors of current DEB.

Methods: Data were taken from 332/218 11- to 27-year-old participants (55.7% girls/women, mean age [SD] 17.8 [3.4] years, mean diabetes duration 14.9 [3.0] years) of two/three surveys of a Germany-wide longitudinal study on early-onset and long duration diabetes, respectively. A diabetes-adapted version of the SCOFF questionnaire was used to assess DEB. Both screening-based overall and age- and sex-specific prevalence of DEB and its symptoms were determined. To estimate transition probabilities between DEB states, first-order Markov transition models were implemented adjusting for previous sociodemographic, socioeconomic, and diabetes-specific covariates.

Results: The overall screening-based DEB prevalence among all 1,318 observations was 10.8% (95% confidence interval [CI]: 9.2%, 12.6%) with age-specific differences in symptom prevalence. Transition probabilities for developing/persistent DEB were twofold higher among female than male participants (risk ratio [RR] 2.3 [1.4, 3.9]/2.1 [1.3, 3.4]). In multiple adjusted regression, previous DEB (odds ratio [OR] 2.8 [95% CI 1.4, 5.6]), follow-up time (OR 3.4 [1.4, 8.0]), and sex (OR 2.1 [1.1, 3.9]) were the most important predictors of current DEB with further weaker associations for previous age and HbA.

Conclusions: Our results contribute to better understanding the course of DEB in patients with early-onset diabetes and emphasize the relevance of regular DEB screenings including the age group of young adults.
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http://dx.doi.org/10.1016/j.jadohealth.2019.05.016DOI Listing
November 2019

CD4 T-Cells With High Common γ Chain Expression and Disturbed Cytokine Production Are Enriched in Children With Type-1 Diabetes.

Front Immunol 2019 24;10:820. Epub 2019 Apr 24.

Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Medical Faculty, Düsseldorf, Germany.

The common gamma chain (γ) contributes to the formation of different cytokine receptors [e.g., IL-2 receptor (IL-2R), IL-7R, and IL-15R], which are important for generation of self-reactive T-cells in autoimmune diseases, like in type 1 diabetes (T1D). Whereas, the roles of membrane and soluble IL-2Rα and IL-7Rα variants in T1D disease pathogenesis are well-described, effects of γ expression and availability for dependent receptors remain elusive. We investigated expression of the γ and dependent receptors on T-cells and soluble γ concentrations in serum from patients with T1D ( = 34) and healthy controls ( = 27). Effector T-cell cytokines as well as IL-2, IL-7, and IL-15 induced STAT5 phosphorylation were analyzed to determine functional implications of differential γ expression of CD4 T-cell subsets classified by t-distributed Stochastic Neighbor Embedding (t-SNE) analyses. We found increased γ and IL-7Rα expression of CD4 T-cells from T1D patients as compared to controls. t-SNE analyses assigned differential expression to subsets of memory T-cells co-expressing γ and IL-7Rα. Whereas, γ expression was positively correlated with IL-2Rα in memory T-cells from healthy controls, no dependency was found for patients with T1D. Similarly, the effector T-cell cytokine, IL-21, correlated inversely with γ expression in healthy controls, but not in T1D patients. Finally, T1D patients with high γ expression had increased proportions of IL-2 sensitive pSTAT5 effector T-cells. These results indicated aberrantly high γ expression of T-cells from T1D patients with implications on dependent cytokine receptor signaling and effector T-cell cytokine production.
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http://dx.doi.org/10.3389/fimmu.2019.00820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499215PMC
September 2020

ZFP57-related Transient Neonatal Diabetes Responsive to Oral Sulfonylurea Treatment.

Klin Padiatr 2019 07 7;231(4):225-226. Epub 2019 May 7.

Department of General Pediatrics, University Children's Hospital Duesseldorf, Duesseldorf.

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http://dx.doi.org/10.1055/a-0889-8307DOI Listing
July 2019

Motivational Interviewing as a tool to enhance access to mental health treatment in adolescents with chronic medical conditions and need for psychological support (COACH-MI): study protocol for a clusterrandomised controlled trial.

Trials 2018 Nov 14;19(1):629. Epub 2018 Nov 14.

Department of General Paediatrics, Neonatology and Paediatric Cardiology, University Children's Hospital, Medical Faculty, Moorenstr. 5, Düsseldorf, 40225, Germany.

Background: This cluster-randomised monocentric controlled trial focuses on improving the uptake symptoms of mental health care in adolescents with chronic medical conditions who have been identified by screening to have depression or anxiety. The study aims to determine the efficacy of motivational interviewing (MI) delivered by trained physicians to increase 12- to 20-year-old adolescents' utilisation of psychological health care for symptoms of anxiety or depression.

Methods/design: In this single-centre approach, n = 1,000 adolescents will be screened (using PHQ-9 and GAD-7), and adolescents with results indicative of anxiety or depressive symptoms (n = 162) will be advised to seek psychological health care in clusters from treating physicians in specialised outpatient departments. Participants who screen positive will receive either two sessions of MI or treatment as usual (TAU; regarded as the typical daily clinical practice), which is focused on recommending them to seek psychological health care for further evaluation. MI efficacy will be compared to the current TAU as the control condition. The primary outcome is the utilisation rate of psychological health care after counselling by an MI-trained physician vs. an untrained physician. Additionally, reasons for not claiming psychological support and changes in disease-related parameters will be evaluated in a 6-month follow-up session.

Discussion: This trial will evaluate the feasibility of MI as a way to improve the utilisation of mental health-care services by adolescents who need further support other than that provided by standard care for chronic diseases. Physicians offering MI to adolescents may serve as a model for optimising health-care management in daily clinical practice, which may improve adolescents' long-term well-being by improving adherence to medical treatment and preventing negative lifelong consequences into adulthood.

Trial Registration: German Trials Register (DRKS), DRKS00014043 . Registered on 26 April 2018. Düsseldorf University study ID: 2017114504.
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http://dx.doi.org/10.1186/s13063-018-2997-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6236943PMC
November 2018

Correction: Reinauer et al., The Clinical Course of Patients with Preschool Manifestation of Type 1 Diabetes Is Independent of the HLA DR-DQ Genotype. Genes 2017, 8, 146.

Genes (Basel) 2018 01 3;9(1). Epub 2018 Jan 3.

Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.

The article entitled "The Clinical Course of Patients with Preschool Manifestation of Type 1 Diabetes is Independent of the HLA DR-DQ Genotype" contained a calculation error in Table 2 and the statistical methods used were not completely described.[...].
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http://dx.doi.org/10.3390/genes9010013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5793166PMC
January 2018

Relationship of Serum Fetuin A with Metabolic and Clinical Parameters in German Children and Adolescents with Type 1 Diabetes.

Horm Res Paediatr 2018 5;89(2):73-81. Epub 2017 Dec 5.

Department of General Pediatrics, Neonatology, and Pediatric Cardiology, University Children's Hospital, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

Background And Aim: The hepatokine fetuin A is upregulated in the metabolic syndrome and in type 2 diabetes (T2D), while its role in adolescent type 1 diabetes (T1D) is unclear. We assessed the relationship between circulating fetuin A levels and metabolic control, comorbidities, and complications in adolescent T1D patients.

Methods: We studied the relationship between serum fetuin A and clinical diabetes-related data from the DPV registry (Diabetes-Pa-tienten-Verlaufsdokumentation) in 172 adolescent T1D patients with early-onset (<5 years) long-standing (>10 years) T1D. Fetuin A levels were further compared between adolescent T1D and T2D patients.

Results: Serum fetuin A levels in T1D patients (mean 0.267 ± 0.043 g/L) did not correlate with age, diabetes duration, gender, body mass index (BMI), glycated hemoglobin, serum lipid levels, blood pressure, celiac or thyroid disease, nephropathy, or retinopathy. An association of fetuin A levels with insulin requirements was only evident within the subgroup of overweight T1D patients (rs = 0.439, p = 0.028, n = 25, BMI >90th percentile), disappearing after adjustment for multiple testing. Adolescent T1D patients showed distinctly lower fetuin A levels than patients with T2D (p ≤ 0.001).

Conclusion: Overall, we did not observe a clinically relevant association of fetuin A levels with surrogate parameters for insulin sensitivity in our juvenile T1D cohort. A correlation with insulin requirements was detectable in overweight patients only. We hypothesize that multiple factors, such as obesity, puberty, inadequate metabolic control, and hepatic steatosis, have to add up before a clinically relevant effect of fetuin A on insulin sensitivity becomes evident.
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http://dx.doi.org/10.1159/000484896DOI Listing
September 2018

Lipoprotein-associated phospholipase A2 activity in obese adolescents with and without type 2 diabetes.

J Inherit Metab Dis 2018 01 13;41(1):73-79. Epub 2017 Oct 13.

Department of General Pediatrics, Neonatology, and Pediatric Cardiology, University Children's Hospital, Medical Faculty, 40225, Düsseldorf, Germany.

Lipoprotein-associated phospholipase A2 (Lp-PLA2) was identified as a strong predictor for cardiovascular events. Furthermore, it is highly associated with obesity. The role of Lp-PLA2 in diabetes mellitus is controversial and analyses, especially in adolescents with type 2 diabetes (T2D), are missing. Therefore, we compared Lp-PLA2 activity between two obese age-, sex-, and BMI-matched cohorts of adolescents with and without T2D. Relationships between Lp-PLA2 activity and age, BMI, hemoglobin A1c, lipids, and adipokines were evaluated. Lp-PLA2 activity was analyzed in serum of 72 obese adolescents without T2D (mean age 15.2 ± 1.6 years) and in 65 obese adolescents with T2D (mean age 15.5 ± 1.8 years). Clinical data were obtained from the Diabetes-Patienten-Verlaufsdokumentation (DPV) registry. Surprisingly, obese adolescents with T2D had lower levels of Lp-PLA2 activity than obese children without T2D (160.2 ± 45.0 versus 180.9 ± 35.6 nmol/min/ml, p = 0.003), but this decrease could only be detected in male (158.8 ± 45.3 versus 190.8 ± 31.3 nmol/min/ml, p < 0.001) and not in female adolescents (162.1 ± 45.5 versus 167.7 ± 37.1 nmol/min/ml, p = 0.60). In multiple linear regression analysis, differences in Lp-PLA2 activity between cohorts remained large and significant (ß-coefficient: -31.60, 95% confidence interval [-49.27;-13.93], p < 0.001). Furthermore, Lp-PLA2 activity was positively associated with BMI (ß-coefficient: 2.04 [0.68;3.40], p = 0.004) and negatively associated with the adipokines leptin (ß-coefficient: -0.53 [-0.89;-0.17], p = 0.004) and adiponectin (ß-coefficient: -3.06, [-5.63;-0.48], p = 0.02). Elevated mean glucose concentrations in adolescents with T2D were not associated with an increase but with a decrease of Lp-PLA2 activity. Hence, in young patients with T2D the Lp-PLA2 activity as a risk predictor for cardiovascular events needs further investigation.
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http://dx.doi.org/10.1007/s10545-017-0100-0DOI Listing
January 2018

Polycystic Ovary Syndrome (PCOS) in Juvenile and Adult Type 1 Diabetes in a German/Austrian Cohort.

Exp Clin Endocrinol Diabetes 2017 Nov 19;125(10):661-668. Epub 2017 Sep 19.

Institute of Epidemiology and Medical Biometry, ZIBMT, University of Ulm, Ulm, Germany.

While an association between PCOS and type 2 diabetes is well established, to date there have been few data on clinical care of type 1 diabetes (T1D) patients with PCOS. The aim of our study was to characterize T1D patients with the comorbidity of PCOS within the DPV cohort with regard to diabetes phenotype, therapy and metabolic control. Clinical data from the prospective German/Austrian DPV cohort on patients with T1D and documented PCOS (n=76) were compared to female T1D controls (n=32,566) in reproductive age. The age at T1D manifestation in PCOS patients was later than in the control group (14.9±8.2 vs. 11.8±7.0 years, p<0.001). PCOS patients had higher BMI-SDS (0.92±0.11 vs. 0.38±0.01, p<0.001), metformin and oral contraceptives were used more frequently (p<0.001). A1c levels were significantly lower (7.92 +/- 0.23% vs. 8.43±0.01%, p<0.05) despite of lower insulin requirements (0.76±0.04 IU/kg/d vs. 0.84±0.00 IU/kg/d, p<0.05). In the PCOS group, higher rates of dyslipidemia (63.4 vs. 48.7%, p =0.032) and thyroid disorders (42.2% vs. 21.2%, p<0.001) were present. While patients with T1D and comorbid PCOS showed features of a "type 1.5 diabetes" phenotype, insulin requirements per kg body weight were not higher and metabolic control was better, which could be explained only partially by additional metformin therapy. A more precise genetic and metabolic characterisation of these patients is needed to answer open questions on the underlying autoimmune process and residual ß-cell function.
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http://dx.doi.org/10.1055/s-0043-104701DOI Listing
November 2017

The Clinical Course of Patients with Preschool Manifestation of Type 1 Diabetes Is Independent of the HLA DR-DQ Genotype.

Genes (Basel) 2017 May 19;8(5). Epub 2017 May 19.

Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.

Introduction: Major histocompatibility complex class II genes are considered major genetic risk factors for autoimmune diabetes. We analysed Human Leukocyte Antigen (HLA) and haplotypes in a cohort with early-onset (age < 5 years), long term type 1 diabetes (T1D) and explored their influence on clinical and laboratory parameters.

Methods: Intermediate resolution , and typing was performed in 233 samples from the German Paediatric Diabetes Biobank and compared with a local control cohort of 19,544 cases. Clinical follow-up data of 195 patients (diabetes duration 14.2 ± 2.9 years) and residual C-peptide levels were compared between three HLA risk groups using multiple linear regression analysis.

Results: Genetic variability was low, 44.6% (104/233) of early-onset T1D patients carried the highest-risk genotype ( denoting ), and 231 of 233 individuals carried at least one of six risk haplotypes. Comparing clinical data between the highest ( = 83), moderate ( = 106) and low risk ( = 6) genotypes, we found no difference in age at diagnosis (mean age 2.8 ± 1.1 vs. 2.8 ± 1.2 vs. 3.2 ± 1.5 years), metabolic control, or frequency of associated autoimmune diseases between HLA risk groups (each > 0.05). Residual C-peptide was detectable in 23.5% and C-peptide levels in the highest-risk group were comparable to levels in moderate to high risk genotypes.

Conclusion: In this study, we saw no evidence for a different clinical course of early-onset T1D based on the HLA genotype within the first ten years after manifestation.
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http://dx.doi.org/10.3390/genes8050146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5448020PMC
May 2017

Reply to: mitochondrial diabetes in Germany and Austria.

Eur J Pediatr 2016 12 23;175(12):2025-2026. Epub 2016 Sep 23.

Institute of Epidemiology and Medical Biometry, ZIBMT, University of Ulm, German Center for Diabetes Research (DZD), 89081, Ulm, Germany.

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http://dx.doi.org/10.1007/s00431-016-2784-9DOI Listing
December 2016

Low prevalence of patients with mitochondrial disease in the German/Austrian DPV diabetes registry.

Eur J Pediatr 2016 May 15;175(5):613-22. Epub 2015 Dec 15.

Institute of Epidemiology and Medical Biometry, ZIBMT, University of Ulm, German Center for Diabetes Research (DZD), 89081, Ulm, Germany.

Unlabelled: The aim of this study was to characterize the phenotype and treatment of young patients (manifestation <30 years) with diabetes of mitochondrial origin (DMO), based on the German/Austrian DPV (Diabetes Patienten Verlaufsdokumentation) registry. Only 13 (0.02 %) of all patients with diabetes in this cohort were identified with DMO, mainly due to the Kearns-Sayre (n = 5), Pearson (n = 3), or mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome (n = 2). The onset of DMO (14.2, interquartile range (IQR) 7.1-16 years) was later than diabetes onset in individuals with T1D but earlier than in T2D. At manifestation, patients exhibited a mild elevation of blood glucose concentrations (251, IQR 178-299 mg/dl) without ketoacidosis. They had lower body mass index (BMI) values (-1.39 ± 0.28 kg/m(2)) than peers with T1D or T2D (p < 0.0001) and higher triglycerides (211, IQR 134-574 mg/dl) than in T1D (p = 0.04) while there was a high rate of dyslipidemia (86 %). Insulin requirements (0.58, IQR 0.37-0.90 U/kg/d) were between T1D and T2D while glucometabolic control (glycated hemoglobin A1c (HbA1c) 7.4 ± 0.52 %) in DMO was comparable to age-matched T2D and stable over a 5-year follow-up.

Conclusion: Primary mitochondrial disorders are a rare cause of juvenile diabetes and likely to be underdiagnosed. As there is clinical overlap with T1D and T2D, dyslipidemia and low body weight may help to identify further DMO cases.

What Is Known: • In adults diabetes of mitochondrial origin (DMO) is a rare cause of non-autoimmune diabetes, affecting about 0.8 % of diabetes cases. • Common features are a maternal family history of diabetes, hearing loss and neurological abnormalities. What is New: • In our juvenile cohort 0.02 % of diabetes patients (age < 30 years) were affected by DMO, while Kearns Sayre, MELAS and Pearson syndrome were the most frequent entities. • Juvenile DMO patients exhibited dyslipidemia, higher triglycerides and a lower BMI than peers with T1D or T2D, while some patients also showed retinal changes.
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http://dx.doi.org/10.1007/s00431-015-2675-5DOI Listing
May 2016

Expression and translation of the COX-1b gene in human cells--no evidence of generation of COX-1b protein.

Biol Chem 2013 Jun;394(6):753-60

Institute for Pharmacology and Clinical Pharmacology, Heinrich-Heine-University, D-40225 Düsseldorf, Germany.

Cyclooxygenase 1b (COX-1b) is a splice variant of COX-1, containing a retained intron 1 within the signal peptide sequence. COX-1b mRNA is found in many species, but the existence of a functionally active protein, which is possibly related to different species-dependent lengths of intron 1, is controversially discussed. The human intron 1 comprises 94 bp, and the resulting frameshift at the intron 1-exon 2 junction creates a premature stop codon. Nevertheless, full-length human COX-1b protein expression, including translated intron 1 and the signal peptide, has been reported and was explained by a frameshift repair. In this study, the fate of COX-1b mRNA in a human overexpression system is analyzed. Independent of the hypothetical frameshift repair mechanism, the splicing of the COX-1b intron 1, resulting in COX-1 mRNA and removal of the signal peptide during protein maturation, with subsequent generation of a COX-1 protein is demonstrated.
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http://dx.doi.org/10.1515/hsz-2012-0309DOI Listing
June 2013